Core A - Variant prioritization and curation core

核心 A - 变体优先级和管理核心

• 批准号: 10247553
• 负责人: EDWARD C COOPER
• 金额: $ 23.01万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247553
• 关键词: Algorithms; American; Archives; Bioinformatics; Catalogs; Classification; ClinVar; Clinical; Clinical Data; Clinical Research; Collaborations; Communities; Complement; Data; Data Element; Data Set; Databases; Diagnostic; Ensure; Epilepsy; Evaluation; Funding; Future; Gene Family; Genes; Genetic; Genetic Research; Genomics; Genotype; Hot Spot; Human; In Vitro; International; Ion Channel; Ion Channel Gating; Knowledge; Laboratories; Medical Genetics; Mission; Mutation; Neurons; Ontology; Outcome Assessment; Pathogenicity; Patients; Phenotype; Process; Prognosis; Protocols documentation; Publications; Recommendation; Recurrence; Research; Research Personnel; Resources; Scientist; Secure; Severities; Source; Standardization; Taxonomy; Terminology; Translating; United States National Institutes of Health; Variant; Work; base; childhood epilepsy; clinical phenotype; early onset; genetic variant; improved; in vivo; induced pluripotent stem cell; medical schools; member; mouse model; novel; precision medicine; prospective; recruit; research study; variant of unknown significance; voltage; web portal

PROJECT SUMMARY – CORE A Variants in ion channel genes represent the most common genetic finding in severe pediatric epilepsies. However, knowledge of the genetic landscape of channelopathy-associated epilepsy is incomplete, owing to the rapid pace of variant discovery and the challenges of variant interpretation. Further, much of the existing relevant knowledge is not widely available, including recently identified variants, associated clinical phenotypes, protocols for variant functional analysis, and best practices for integrating functional, genetic, and clinical data to assess pathogenicity and prognosis. The Variant Prioritization and Curation Core (Core A) will modify and deploy an existing collaborative bioinformatics and variant curation platform to support the mission of our Center. Core A will serve as an interface to ongoing NIH curation efforts, including ClinVar and ClinGen, to ensure that functional data generated by the Center are enduring and fully accessible. In Aim 1, we will catalog variants in the epilepsy-associated voltage-gated ion channel genes. To maximize the utility of in vitro and in vivo functional studies performed in Projects 1-3, Core A will establish and maintain a database of known epilepsy-associated variants in voltage-gated ion channel genes. We will assemble genetic and phenotypic information from diverse sources including publications, locus-specific databases, previously undisclosed data from diagnostic laboratories (~30,000 patients) and research studies (~20,000 subjects). In Aim 2, we will prioritize variants in ion channel genes for functional evaluation. Ion channel gene variants of the highest clinical importance and analytical validity will be selected for the high-throughput studies proposed in Project 1. To identify which variants meet this standard, we will apply a range of criteria including established American College of Medical Genetics and Genomics (ACMG) diagnostic rules and an advanced data-driven algorithm that considers mutational ‘hot spots,’ gene family information, and regional intolerance. Based on the applied criteria, we will prioritize 1,000 variants for functional evaluation over the 5-year funding period. In Aim 3, we will use functional data to iteratively refine variant classifications and diagnostic criteria. We will apply results from the Center to propose improved classification rules for variants and work within the ClinGen consortium to develop a gene/variant-based taxonomy of early onset epilepsy that harmonizes with the International League Against Epilepsy (ILAE) classification and terminology. To ensure public access, Core A members will expand their ongoing collaboration with the NIH-funded ClinGen consortium, and the ClinVar archive by submitting all classified ion channel variants and key supporting evidence to ClinVar as an Expert Panel. As part of this effort, we will augment existing ClinVar data elements to include data fields on variant function using an ontology developed by Project 1.

项目摘要 - 核心A 离子通道基因中的变体代表了严重的小儿癫痫中最常见的遗传发现。 然而，了解与通道病相关癫痫的遗传景观是不完整的 变体发现的快速速度和变体解释的挑战。此外，许多现有 相关知识并非广泛可用，包括最近确定的变体，相关的临床 表型，用于变异功能分析的方案以及整合功能，遗传和 评估致病性和预后的临床数据。变体优先级和策展核（核心A）将 修改和部署现有的协作生物信息学和变体策划平台，以支持任务 我们的中心。核心A将作为正在进行的NIH策划工作的界面，包括Clinvar和Clingen， 为了确保中心生成的功能数据持久且完全访问。 在AIM 1中，我们将在与癫痫相关的电压门控通道基因中分类。最大化 在项目1-3中进行的体外和体内功能研究的实用性，核心A将建立和维护 电压门控离子通道基因中已知癫痫相关变体的数据库。我们将组装遗传 以及来自包括出版物，基因座特定数据库在内的潜水资源的表型信息，以前 来自诊断实验室（约30,000名患者）和研究（约20,000名受试者）的未公开数据。在 AIM 2，我们将优先考虑离子通道基因中的变体进行功能评估。离子通道基因变体 对于提出的高通量研究，将选择最高的临床重要性和分析有效性 项目1。为了确定哪些变体符合此标准，我们将应用一系列标准，包括已建立 美国医学遗传学学院（ACMG）诊断规则和先进的数据驱动 考虑突变的“热点”，基因家族信息和区域性intlerance的算法。基于 应用标准，我们将在5年的资金期间优先考虑1,000个用于功能评估的变体。目标 3，我们将使用功能数据来迭代完善变体分类和诊断标准。我们将申请 中心的结果提出了改进的变体的分类规则，并在Clingen内部工作 联盟开发基于基因/变体的早期发作癫痫的分类法，该分类癫痫与 国际反对癫痫联盟（ILAE）分类和术语。为了确保公众访问，请核心A 会员将扩大与NIH资助的克林根联盟和Clinvar的持续合作 通过将所有分类离子频道变体和关键证据提交给Clinvar作为专家的档案 控制板。作为这项工作的一部分，我们将增强现有的Clinvar数据元素，以包括变体的数据字段 功能使用项目1开发的本体学。